EXCEED THE SPACE PROVIDED. The broad goal of this project has been to elucidate some of the cellular substrates of neuronal memory storage. Memory is a basic function of the human brain and diseases of memory are responsible for enormous emotional and economic losses to society. A central hypothesis of modern neurobiology is that memory is stored through use-dependent changes in synaptic strength. Most work in this area has focused upon long-term potentiation and depression (LIP and LTD) of glutamatergic synapses. One limitation of this approach is that the brain regions where LIP and LTD are most often studied, such as the hippocampus, receive information that is so complex that its content cannot be easily characterized. In contrast, in the cerebellum it has been possible to propose a "circuit diagram" for some simple forms of learning such as associative eyeblink conditioning. Over the last 20 years, a series of experiments which have used behavioral tasks together with extracellular recording, reversible inactivation and transgenic manipulations have produced a strong case that the cerebellum is critical for these forms of motor learning. In particular, LTD and LTP of excitatory synapses received by cerebellar Purkinje cells have been implicated. Here, we propose to extend our detailed molecular characterization of this model system for memory by adressing the following questions: How does phosphorylation of GluR2 ser-880 ultimately result in the expression of cerebellar LTD? What are the molecular mechanisms which underlie LTP of glutamate transporter currents? What are the structural correlates of LTP and LTD in excitatory synapses received by Purkinje cells? This will be accomplished through a combination of electrophysiology, imaging and molecular manipulation with biochemical and genetic tools. This is basic reaserch to illuminate the molecular mechanims that underlie memory storage, using what we believe to be an unusually promising model system. It is hoped that this work will ultimately be useful for creating therapies and diagnostics for diseases of memory. Because these processes by which synaptic strength is persisitently modulated are not only involved in memory storage, this work has potential implications for other brain diseases as well, including Fragile X mental retardation, epilepsy and addiction.